Vol.48,No.12,2021
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Cover Story：Calcium homeostasis modulator 2 (Calhm2) is involved in the modulation of Ca2+ activity and ATP
release. Our previous work has demonstrated that Calhm2 plays a crucial role in the progression of depression by
regulating the astrocytic ATP release. In order to further explore the role and mechanism of Calhm2 in the
development of depression, we firstly predicted the ATP binding site (glutamine, amino acid 87) of Calhm2, and
established a mouse line that carried calhm2 mutation by mutating the glutamine to alanine (Q87A). Secondly, by
using the primary culture of astrocyte and ATP detection analysis, we found that Calhm2 Q87A mutation resulted
in a significant decrease of ATP release in astrocytes. Furthermore, we found that the ATP release decreased in
hippocampal slice from Calhm2 Q87A mutated mice. Importantly, Calhm2 Q87A mutated mice showed a higher
susceptibility to develop depression-like symptoms than that of wild type mice when exposed to chronic
unpredictable mild stress (CUMS). Taken together, we identified that Q87 site is important for Calhm2-mediated
ATP release in astrocytes and this point mutation of Calhm2 promotes depression susceptibility induced by stress
in mice. The present work further defines the molecular mechanism of Calhm2 in the development of depression,
with the implication of a potential avenues for the diagnosis and therapeutics of depression-related diseases.
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Interpretation of the Nobel Prize in Physiology or Medicine 2021
Special Topic: Depression Research
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